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Annals of Biotechnology
Open Access | Editorial

Anthracycline-induced cardio toxicity: Posing the

right questions to find the correct answers
*Corresponding Author(s): Yuri D’ Alessandra,

Immunology and Functional Genomics Unit, Centro

Cardiologico Monzino, via Parea 4, 20138 Milan, Italy

Phone: +39-02-5800-2852, Fax: +39-02-5800-2750

Email: ydalessa@ccfm.it

Received: Jan 08, 2018

Accepted: Jan 26, 2018
Published Online: Feb 05, 2018
Journal: Annals of Biotechnology
Publisher: MedDocs Publishers LLC
Online edition: http://meddocsonline.org/
Copyright: © Alessandra Y (2018). This Article is distributed
under the terms of Creative Commons Attribution 4.0 interna-
tional License

Cardio toxicity in oncologic patients and late consequences. In the last years, the term Cardioncol-
ogy has been coined to describe a new medical discipline with
Anthracyclines, such as Doxorubicin (Dox), are among the
the aim of dealing with this important clinical need [6]. Anthra-
most effective anti-cancer agents but their clinical use is limited
cycline-induced cardio toxicity may manifest itself months or
by cumulative dose-dependent cardiac toxicity, which leads to
years after chemotherapy and can be categorized, by the time
untreatable heart failure (HF) in a high percentage of patients.
of presentation as acute, early-onset or late-onset. In acute an-
The primary problem posed by the harmful effects of these
thracycline cardio toxicity, symptoms manifest within hours or
drugs are that their long-term use is impaired, leading to an
days of administration, often presenting as disturbances in in-
incomplete exploitation of their anti cancer potential [1]. With
tracardiac conduction and arrhythmias. In rare cases, pericardi-
increasing long-term cancer survivors, the number of patients
tis and acute left ventricular (LV) failure can also occur [7]. Early-
experiencing anthracycline induced cardio toxicity is expected
onset anthracycline-induced cardiac damage occurs within [1]
to grow [2]. According to estimates, there are, at present, sev-
year of treatment, and late-onset damage occurs ≥ 1 year after
eral millions of cancer survivors in Western countries [3], many
treatment. Early- and late-onset cardio toxicity are character-
of which underwent chemotherapy treatments, thus being at
ized by progressive LV dysfunction ultimately leading to HF. In
risk of potential long-term cardiovascular toxicities. Indeed,
many patients, subclinical echocardiographic abnormalities of
the risk of cardiovascular death in these patients is higher than
LV structure and function are found in the first few years after
the actual possibility of tumor recurrence [4] with a seven-fold
anthracycline exposure, indicating that most patients experi-
higher cardiac mortality rate in childhood cancer survivors [5].
ence cardiac injury soon after anthracycline administration and
The early identification of patients at risk for cardio toxicity is a
that the consequences of this injury worsen over time [8,9]. Sus-
current need for both oncologists and cardiologists, in order to
ceptibility to toxicity varies in each patient suggesting possible
counteract the development of cardiac impairment and its early
genetic-based differences in processing anthracyclines [10].

Cite this article: Alessandra Y. Anthracycline-induced cardio toxicity: Posing the right questions to find the
correct answers. Ann Biotechnol. 2018; 1(1): 1001.

1

Cardio toxicity definition and assessment: A matter of the
left ventricle
Despite the establishment of the harmful effect exerted by
anthracyclines on the heart being now well in the past, there is
still a huge controversy about the real definition of cardio tox-
icity. This issue is of no small consequence because it affects
not only the way in which patients are treated, but also the
way in which the research of new markers of toxicity is con-
ducted. Indeed, the definition of cardio toxicity used in clinical
and research settings can vary among different institutes. One
widely accepted classification used in oncology is defined by
the Cardiac Review and Evaluation Committee on trastuzumab-
associated cardio toxicity and the ESMO Clinical Practice Guide-
lines. Cardio toxicity is defined as “a decrease of LVEF by 5% or
more to less than 55% in the presence of symptoms of HF or an
a symptomatic decrease in LVEF by 10% or more to less than
55%” [11]. Indeed, cardio toxicity can be defined as any heart
injury (functional or structural) related to cancer treatment, and
it usually equates (although not always) with the presence of
left ventricular disease and HF onset. The ESC European Guide-
lines for the diagnosis and treatment of HF, published in 2016,
classified HF into: reduced left ventricular ejection fraction
(LVEF<40%), mid-range ejection fraction (LVEF 40-49%) and pre-
served ejection fraction (LVEF >50%) [12]. Many cardio toxicity-
affected patients show HF with reduced ejection fraction, but
there are probably also patients presenting HF with preserved
ejection fraction. Indeed, currently there are clinical trials in-
vestigating the actual incidence of HF with preserved ejection
fraction. Interestingly, in the last years, an increasing interest
was registered regarding the effects of anthracyclines on right
ventricular (RV) and left atrial (LA) function. The investigations
involving the RV showed controversial results. Indeed, in some
instances, partial functional impairment was detectable in pa-
tients even before treatment, possibly because of detrimental
cardiac effects of the tumor itself. Additional studies, however,
evidenced a negative effect of the drug on RV systolic function
and remodeling.
Beside the RV, recent investigations clearly showed the func-
tional impairment of the LA upon anthracycline treatment,
thus introducing a new possible way of defining and diagnosing
cardio toxicity. In particular, Shi and co-workers evidenced that
early LA functional changes, detected by real-time three-dimen-
sional echocardiography, can occur after doxorubicin exposure
even inpatients with preserved LVEF [13]. Similarly, Yaylali et al.
observed electromechanical delay (a predictor of atrial fibrilla-
tion measured by echocardiography) and mechanical function
impairment after anthracycline-containing chemotherapy. The
authors concluded that impaired left atrial electrical conduction
could contribute to the development of atrial arrhythmias [14].
Circulating biomarkers of cardio toxicity
The current approach for detecting cardiotoxicity, based on
the assessment of cardiac performance and cardiologic surveil-
lance during and after chemotherapy completion by the evalu-
ation of LVEF is not adequate for early stage assessment. This is
largely due to the absence of a detectable change in LVEF until a
critical amount of myocardial cell loss has already occurred. At
that time cardiac damage is already present and, in most cases,
not reversible, thus precluding any chance of preventing its
development [15]. Indeed, complete recovery of cardiac func-
tion occurs in only around 40% of patients with chemotherapy-
induced cardiomyopathy [16]. In addition, the evidence of a
normal LVEF does not exclude the possibility of a late cardiac
Annals of Biotechnology
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deterioration. The gold-standard marker currently adopted in
the clinical routine to identify patients at risk of cardio toxicity
is cardiac Troponin (cTn). The presence of this protein in the
plasma represents a reliable and quantitative established mark-
er of the extent of myocardial injury. Several studies have dem-
onstrated that cTn (and, to some extent, also BNP) can be used
as a marker for myocardial injury in patients treated with an-
thracyclines and can partially predict the development of future
left ventricular dysfunction, although not the time of its onset
[17]. One limitation of cTn is the need to collect several blood
samples at different time intervals after drug administration. In
addition, very few patients show an increase in cTn levels dur-
ing the first administration of chemotherapy, hinting to a need
of progressive and cumulative damage during and after the
therapy to observe a meaningful change in dysfunction mark-
ers. Further more, the best time point beyond which a negative
value can assure that no further cTn release will occur is not
predictable. The limitations of this marker hint at the need of
new biomarkers to detect the onset of cardiac damage at a very
early phase, possibly during the first cycle of therapy, allowing
an early treatment and a possible increase in recovery rates.
Among all the possible contenders, circulating microRNAs
(miRNA) represent very good candidate for this important task.
miRNAs are short (22 to 24 nucleotides-long) non-coding RNAs,
known to regulate complex biological processes by ‘fine-tuning’
the translation of specific messenger RNA targets [18]. They
are pivotal modulators of mammalian cardiovascular develop-
ment and disease, and can be stably found in the systemic hu-
man circulation and other animal species. Since their levels can
change significantly upon different stimuli, circulating miRNAs
have been successfully used as diagnostic biomarkers for sev-
eral cardiac diseases [19-21] and can act as signaling molecules
in response to specific stimuli and in the absence of cell damage
such as during pregnancy [22]. Although many aspects of circu-
lating and tissue miRNAs role and involvement in several can-
cers have been elucidated, to date there are only few studies
linking circulating microRNAs and anthracycline cardiotoxicity
[23]. One particularly interesting feature of the patient-based
investigations is that cardiotoxicity was defined differently in
each study, both in terms of cardiac damage onset evaluation
(echography/troponin) and in terms of time of assessment post
the initiation of anthracycline treatment. Indeed, the evalua-
tion of miRNAs and other plasma markers was conducted from
hours to months after chemotherapy administration. In these
heterogeneous settings, a correct evaluation of toxicity onset
and the correct identification of new biomarkers can become
very difficult.
Conclusion
Cardiotoxicity is an old and established detrimental side ef-
fect of anthracyclines. Despite that, currently there is no clear
and commonly accepted definition for this phenomenon. In-
deed, the current guidelines for detection and treatment of car-
dio toxicity mostly rely on LV function assessment and on a few
general biomarkers of heart damage and dysfunction. The lack
of uniformity in the clinical assessment and response to cardio
toxicity onset clearly hints to a strong change of direction. For
this reason, future investigations should focus on better under-
standing the different involvement of all cardiac districts in car-
dio toxicity onset, possibly leading to the identification of new
parameters to perform an efficient risk assessment before a real
cardiac functional deficiency can start. In addition, the charac-
terization of novel circulating markers will increase the ability
2

of assessing and answering to the detrimental effects of these
important anti-cancer drugs.
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